This proposal, submitted in response to RFA-AG-05-011, explores the age-related changes of the newly discovered inflammation-derived lipidic aldehydes, atheronal-A and -B. We have recently shown that the atheronals are present in vivo within human atherosclerotic plaque material, plasma and brain tissue. Critically, we have shown that the levels of the atheronals within inflamed arteries are significantly elevated upon leukocyte activation. Furthermore we have shown in vitro that the atheronals have biological effects that make them inflammatory mediators. Furthermore we have shown that the atheronals accelerate the misfolding and aggregation of the neurotoxic beta-amyloid peptide. Atheronals have a plasma half-life in mice of several minutes, are freely diffusible between cells and fluid compartments and can thus can impact distant anatomic sites away from the active location of inflammation. Thus, as byproducts of the chronic inflammation that characterizes atherosclerosis within the vascular endothelium, the atheronals may serve as antagonistic chemical mediators of late life disease, both atherosclerosis progression and Alzheimer's disease (AD). We hypothesize therefore that the atheronals, as inflammatory mediators, may be a chemical link that explains the known epidemiologic convergence between atherosclerosis and AD, two major diseases of aging, and may also serve as an example of how ageing within one organ system can affect another. This R21 proposal outlines research in animal systems to quantify the effect of ageing on atheronal levels, and whether atheronal exposure in early life can impact later life pathophysiological changes. This proposal will investigate the relationships of age-related changes in atheronal levels to physiologic and pathophysiologic ageing changes in organ function by investigating the following three specific aims: ? 1) Specific aim #1 Determine the effect of age and atherosclerosis progression on plasma and vascular tissue levels of the atheronals in two murine models of atherosclerosis, the Apo-E deficient (ApoE-/-) and LDLreceptor deficient (LDL-/-) mouse strains. 2) Specific aim #2 Determine the effect of age and atherosclerosis progression on brain tissue levels of the atheronals in the , ApoE-/- and LDL-/- murine models of atherosclerosis. 3) Specific aim # 3 Determine if early age exposure to atheronals results in an increased severity of the late life ageing disorders of atherosclerosis and Alzheimer's disease in murine models of atherosclerosis, ApoE-/- and LDL-/- and a human APP transgenic mouse model (Jackson labs). ? ? ?
